Stavudine (3′-deoxythymidin-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) is approved by the U.S. Food & Drug Administration for the therapeutic treatment of patients infected with retroviruses. The compound, a nucleoside reverse transcriptase inhibitor, and its preparation are disclosed, for example, in U.S. Pat. No. 4,978,655, issued Dec. 18, 1990. It is known that stavudine is effective in the treatment of infections caused by retroviruses such as murine leukemia virus and human immunodeficiency virus, i.e. HIV; HTLV III/LAV virus (the AIDS virus). Stavudine has enjoyed notable commercial success since its introduction.
In the treatment of HIV infections, it is common for the patient to receive a combination of medicaments. Hence, the patients typically have a very large daily pill burden. It will be appreciated that a reduction in the daily pill burden by even one pill may be significant in this patient population. Ultimately, the reduced pill burden may result in increased patient adherence to their HIV regimens, particularly for the drugs for which a once daily dosing can be implemented. Once daily dosing is important in terms of achieving enhanced patient compliance, improved sustained blood levels of medication, safety and patient convenience, hence patient acceptance.
It has been found in gamma scintigraphy studies that stavudine is well absorbed in the upper intestine. The absorption in the colon is approximately one half that of the small intestine. The optimal formulation would be designed to release approximately 40% of the stavudine in four hours and the remainder over the next twelve to twenty hours. A 100 mg. extended dosage form of stavudine, therefore, would be designed to have the same bioavailability as the commercial 40 mg. immediate release capsules given twice daily. Hence, those skilled in the art will appreciate that stavudine would be amenable to once daily dosing if a suitable extended release formulation could be developed. A problem in the formulation of a suitable extended dosage form of stavudine is its sensitivity to moisture that causes it to hydrolyze, primarily into thymine. This moisture sensitivity has not been a problem with the commercial non-sustained release dosage form of stavudine because it is a dry granulation that is filled into hard gelatin capsules. However, sustained release dosage forms conventionally require different compounding procedures typically including a granulation step involving an aqueous medium. Hence, medicaments that are moisture sensitive, such as stavudine, can present a significant challenge to attempts to formulate them. In accordance with the present invention, a method has been found whereby stavudine can be successfully compounded into an extended release formulation utilizing conventional techniques without appreciable loss of potency due to hydrolysis.